A hallmark pathology of the Alzheimer's Disease (AD) brain is the presence of extracellular senile plaques that are comprised primarily of Aβ peptides (Hardy et al., 2002, Science 297:353-356; Selkoe et al., 2003, Ann. Rev. Pharmacol. Toxicol. 43:545-584) formed after APP is cleaved by β- and γ-secretases (Selkoe et al., 2007, Cell 131:215-221; Dominguez, et al., 2004, Neurodegener. Dis. 1:168-174; Lundkvist et al., 2007, Curr. Opin. Pharmacol. 7:112-118). Certain familial forms of AD (Tanzi et al., 2001, Neuron 32:181-184; St. George-Hyslop et al., 2005, C. R. 328:119-130) are caused by mutations within APP that result in an increased production of both Aβ1-40 and Aβ1-42 or in the ratio of the more amyloidogenic Aβ1-42 relative to Aβ1-40. Other inherited cases of AD result from mutations in presenilin 1 (PS1) or PS2 that are integral to γ-secretase activity, with a resulting increase in Aβ1-42 production. The genetic evidence linking familial AD mutations to alterations in Aβ production has strengthened substantially the “amyloid” hypothesis of AD pathogenesis, although the cause of Aβ deposition in sporadic AD is still not fully understood. Moreover, there is still uncertainty about how Aβ contributes to the neurodegeneration observed in AD, and a number of hypotheses have been forwarded ranging from direct toxic effects of Aβ oligomers (Watson, et al., 2005, Neurol. Res. 27:869-881; Walsh, et al., 2002, Biochem. Soc. Trans. 30:552-557; Walsh et al., 2005, Biochem. Soc. Trans. 33:1087-1090) or fibrils (Lorenzo et al., 1996, Neurobiol. Alzheimer's Dis. 777:89-95) to indirect mechanisms whereby multimeric Aβ leads to increased inflammation (McGeer et al., 2001, Neurobiol. Aging 22:799-809; Benzing, et al., 1999, Neurobiol. Aging 20:581-589; Yates, et al., 2000, J. Neurochem. 74:1017-1025) and/or oxidative stress (Chauhan et al., 2006, Pathophysiology 13:195-208; Sayre, et al., 2008, Chem. Res. Toxicol. 21:172-188; McDonald, et al., 1997, J. Neurosci. 17:2284-2294). Gaining a better understanding of the causes of pathologic Aβ formation and how it triggers neurodegeneration could reveal new therapeutic approaches for AD.
There is compelling evidence that the AD brain is under significant oxidative stress (Sayre, et al., 2008, Chem. Res. Toxicol. 21:172-188), as illustrated by a marked elevation of oxidized lipids (Montine, et al., 2004, Chem. Phys. Lipids 128:117-124; Pratico, et al., 2000, Ann. Neurol. 48:809-812; Forman, et al., 2007, Neurology 68:757-763; Markesbery et al., 2007, Arch. Neurol. 64:954-956) including the F2α-isoprostanes, iPF2αIII and iPF2αVI, which are stable non-enzymatic products of free radical damage to arachidonic acid. Both brain tissue and cerebrospinal fluid (CSF) from patients with AD and mild cognitive impairment (MCI) (Montine, et al., 2004, Chem. Phys. Lipids 128:117-124; Pratico, et al., 2000, Ann. Neurol. 48; 809-812; Forman, et al., 2007, Neurology 68:757-763; Markesbery, et al., 005, Ann. Neurol. 58: 730-735; Casadesus, et al., 2007, Mol. Neurodeg. 2:2-9) have increased iPF2α, which might serve as an early marker of AD neuropathology. This interpretation is bolstered by data showing a significant longitudinal elevation of CSF iPF2α in MCI patients over a 2-year interval (de Leon, et al. 2006, Neurobiol. Aging. 27:394-401; Brys, et al., 2009, Neurobiol. Aging. 30:682-690). Significantly, iPF2α levels are also elevated in the well-established Tg2576 transgenic mouse model of AD and, importantly, this increase precedes the appearance of Aβ deposits (Pratico, et al., 2001, J. Neurosci. 21:4183-4187). These observations further suggest that brain oxidation is an early event in AD pathogenesis.
Aβ can form redox complexes with metals like copper that might directly lead to oxidative reactions (Smith, et al., 2007, Biochim. Biophys. Acta 1768:1976-1990; Donnelly, et al., 2007, Curr. Opin. Chem. Biol. 11:128-133). Moreover, activated microglia residing in proximity to senile plaques can release a variety of pro-inflammatory and oxidative agents, including superoxide anions and nitric oxide (Yates, et al., 2000, J. Neurochem. 71:1017-1025; McDonald, et al., 1997, J. Neurosci. 17:2284-2294; McGeer et al., 2001. Neurobiol. Aging 22:799-809; Block et al., 2007, Nat. Rev. Neurosci. 8:57-69). The elevation of iPF2α in MCI patients (de Leon, et al., 2006, Neurobiol. Aging. 27:394-401; Brys, et al., 2009, Neurobiol, Aging) 30:682-690) and Tg mice prior to Aβ plaque development (Pratico, et al., 2001, J. Neurosci. 21:4183-4187) suggest that early oxidative events may spur further pathological changes in the AD brain. In fact, important recent studies (Shineman, et al., 2008, J. Neurosci. 28:4785-4794) reveal that the formation of iPF2α in Tg2576 mice that express mutated human APP can trigger a further up-regulation of Aβ production. iPF2αIII can initiate a specific biological effect through activation of the thromboxane A2 (TxA2) receptor (also referred to as the TP receptor) (Audoly, et al., 2000, Circulation 101:2833-2840; Elmhurst, et al., 1.997, J. Pharmacol. Exp. Ther. 282:1198-1205), and iPF2αIII binding to neuronal TP receptors results in an elevation of APP via stabilization of APP mRNA, with a consequent increase of Aβ release (Shineman, et al., 2008, J. Neurosci. 28:4785-4794). Moreover, long-term treatment of Tg2576 mice with a known TP receptor antagonist, S-18886, caused a significant diminution of plaque load relative to untreated mice. In addition to iPF2α, TxA2 itself may also be up-regulated in the AD brain as a result of its release from activated microglia (Benzing, et al., 1999, Neurobiol. Aging 20:581-589; McGeer et al., 2001, Neurobiol. Aging 22:799-809; Giulian, et al., 1996. Neurochem. Int. 29:65-76; Slepko, et al., 1997, J. Neurosci. Res. 49:292-300). Thus, there is evidence that TP receptors play an important role in AD disease progression by increasing Aβ production in response to both brain oxidation and inflammation. The TP receptor, a member of the highly-druggable G-protein coupled receptor (GPCR) family, is therefore a rational AD therapeutic target.
The discovery and development of TxA2 receptor antagonists (also referred to as TP receptor antagonists) has been an objective of many pharmaceutical companies for approximately 30 years (Dogne J-M, et al., Exp. Opin. Ther. Patents 11: 1663-1675 (2001)). Preclinical pharmacology has established that this class of compounds has effective antithrombotic activity obtained by inhibition of the thromboxane pathway. These compounds also prevent vasoconstriction induced by TxA2 and other prostanoids that act on the TxA2 receptor within the vascular bed. Unfortunately, however, the Phase II/III trials of TxA2 antagonists have not proven successful, and none of these compounds have reached the marketplace in the United States.
There remains a need in the art for identifying novel therapeutic agents that are useful in preventing or treating AD in a mammal. The present invention fills this need.